Effect of Fenofibrate on Oxidative DNA Damage and on Gene Expression Related to Cell Proliferation and Apoptosis in Rats

Nishimura, Jihei; Dewa, Yasuaki; Muguruma, Masako; Kuroiwa, Yoshihiro; Yasuno, Hiroaki; Shima, Tomomi; Jin, Mailan; Takahashi, Miwa; Umemura, Takashi; Mitsumori, Kunitoshi

doi:10.1093/toxsci/kfm011

Cited by 51 publications

(37 citation statements)

References 37 publications

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“…Conversely, in the present study, we demonstrated that the incidence of altered hepatocellular foci, and the number and area of GST-P positive foci markedly increased in rats treated orally with DHP at 1,000 and 2,000 mg/kg/day over a 26-week period. DHPinduced altered hepatocellular foci are composed of eosinophilic or basophilic hepatocytes, and may be characteristic of DHP treatment, since oral administration of common PPARα agonists induced altered foci with eosinophilic cytoplasm in rodents (Moody and Reddy, 1978;Nishimura et al, 2007). Therefore, altered foci with eosinophilic cytoplasm may be GST-P negative foci, but there was no clear relationship between GST-P positive and eosinophlic/basophilic altered foci in the present study.…”

Section: Discussioncontrasting

confidence: 51%

Twenty-six-week oral toxicity of diheptyl phthalate with special emphasis on its induction of liver proliferative lesions in male F344 rats

Nakane¹,

Kunieda²,

Shimizu³

et al. 2012

J. Toxicol. Sci.

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(Mannaerts et al., 1993). PPARs are members of the steroid hormone receptor superfamily, and three related isotypes, specifically PPARα, PPARβ and PPARγ, have been identified (Desvergne and Wahli, 1999). Based on target gene expression patterns, PPARα appears to have critical roles in the regulation of fatty acid metabolism, including fatty acid β-oxidation, apolipoproteins, and fatty acid transport proteins (Lee et al., 1995;Auwerx et al., 1996;Aoyama et al., 1998;Peters et al., 1997;Ren et al., 1997;Martin et al., 1997). Additionally, chronic exposure to numerous PPARα agonists has been reported to increase the incidence of hepatocellular tumors in rodents ABSTRACT -The 26-week oral toxicity of diheptyl phthalate (DHP), a peroxisome proliferator-activated receptor α (PPARα) agonist, with special emphasis on the potential induction of hepatocellular proliferative lesions was investigated in this study. DHP was administered to male F344 rats via gavage at 0 (control), 1,000 or 2,000 mg/kg/day for 26 weeks. Body weight gain was significantly lower, whereas food and water consumption was significantly higher in DHP-treated rats compared with controls. DHPtreated rats exhibited decreases in blood triglyceride, total cholesterol, phospholipid and glucose levels, which were likely related to biological effects of the PPARα agonist. Absolute and relative organ weights of the livers with pale brown discoloration and dark brown spots significantly increased in DHP-treated rats. Histopathological examinations revealed remarkable diffuse hypertrophy of hepatocytes with groundglass appearance, intracytoplasmic inclusion bodies and/or vacuolation in the DHP-treated groups. These findings were associated with increases in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and γ-glutamyltranspeptidase. The number and area of glutathione S-transferase placental form positive foci, a marker of hepatocellular preneoplastic lesions in rats, significantly increased in DHP-treated groups. Additionally, proliferating cell nuclear antigen positive liver cell counts in DHPtreated groups were significantly higher than those of the controls. Testicular alterations were not detected histopathologically, whereas absolute and relative prostate weights significantly decreased at both doses. These results indicate that DHP induces liver pre-neoplastic foci, and suggest the possibility that DHP is a possible genotoxic carcinogen in the liver of rats.

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Section: Discussioncontrasting

confidence: 51%

Twenty-six-week oral toxicity of diheptyl phthalate with special emphasis on its induction of liver proliferative lesions in male F344 rats

Nakane¹,

Kunieda²,

Shimizu³

et al. 2012

J. Toxicol. Sci.

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“…In an initial study, GPX2 mRNA was readily detected in human liver, whereas its orthologs in rats and mice were only found in the intestinal tract (Chu et al, 1993). However, in more recent studies Gpx2 mRNA was also detected in rat liver, for example, by Nishimura et al (2007).…”

Section: Levels Of Xmes In Liver and Intestine Of Control Animalsmentioning

confidence: 89%

Impact of Gut Microbiota on Intestinal and Hepatic Levels of Phase 2 Xenobiotic-Metabolizing Enzymes in the Rat

Meinl¹,

Sczesny²,

Brigelius‐Flohé³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Using immunoblotting, we compared levels of phase 2 enzymes in liver, small intestine, cecum, and colon of germ-free and control rats (reassociated with rat intestinal microbiota). In addition, colonic levels were studied after association with human intestinal microbiota. The glutathione transferases (GSTs) studied, gastrointestinal glutathione peroxidase (GPX2), both epoxide hydrolases (EPHXs), and N-acetyltransferase (NAT) 1, were detected in all tissues. GPX2 and GSTP1 were highest in large bowel; the other enzymes of this group were highest in liver. NAT2 was found in the large bowel but not in the liver or small bowel. Sulfotransferases (SULTs) were detected in liver but were absent in small intestine; two forms were present at moderate levels in the large intestine. Strong gender-dependent differences were observed for several enzymes in liver but not in gut. Colonic levels in germ-free animals differed from those in control animals (* indicates statistical significance) for GSTA1/2 (4.0*-and 5.0*-fold in males and females, respectively), GSTA4 (1.5*/1.9*-fold), GSTM1 (1.1/1.5*-fold), EPHX1 (3.5*/2.4*-fold), EPHX2 (1.4/2.1*-fold), SULT1B1 (0.4*/0.6*-fold), SULT1C2 (1.3/1.6*-fold), and NAT2 (1.4/1.5*-fold). Smaller effects were observed when rats were colonized with human, compared with rat, intestinal bacteria. Cecal enzyme levels in germ-free rats were changed similarly to those in colon. No effects were seen in small intestine. In liver, SULT1A1, SULT1C1, and SULT1C2 were elevated in germ-free animals of both genders (1.5-to 2.6-fold); hepatic EPHX2 was elevated 1.6-fold in females. In conclusion, intestinal microbiota can affect levels of xenobiotic-metabolizing enzymes in large intestine and liver, but the effects observed were moderate compared with tissue-dependent expression differences.

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“…Also, PCB increases CYP1A1-dependent microsomal ROS production (Schlezinger et al, 2006). So far, we have demonstrated that several CYP1A inducers, including oxfendazole, BNF, fenofibrate, piperonyl butoxide, and indole-3-carbinol (I3C), have liver tumor promoting activities in a two-stage hepatocarcinogenesis model in rodents Shoda et al, 2000;Dewa et al, 2008;Nishimura et al, 2007;Kawai et al, 2010;Shimamoto et al, 2011a). These chemicals induce ROS generation in the microsomal fractions; this ROS generation is suspected of enhancing liver tumor promotion by altering cellular physiological functions, such as oxidative proteins, lipid peroxidation, DNA damage and cell signaling Dewa et al, 2008;Nishimura et al, 2007, Kawai et al, 2010Shimamoto et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%

Antioxidant N-acetyl-L-cysteine (NAC) supplementation reduces reactive oxygen species (ROS)-mediated hepatocellular tumor promotion of indole-3-carbinol (I3C) in rats

et al. 2011

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-Indole-3-carbinol (I3C) has a liver tumor promoting activity in rats, and is also known as a cytochrome p450 1A (CYP1A) inducer. The generation of reactive oxygen species (ROS) resulting from CYP1A induction due to I3C, is probably involved in the tumor promotion. To clarify whether ROS generation contributes to I3C's induction of hepatocellular altered foci, partially hepatectomized rats were fed a diet containing 0.5% of I3C for 8 weeks with or without 0.3% N-acetyl-L-cysteine (NAC), an antioxidant, in their drinking water after N-diethylnitrosamine (DEN) initiation. Immunohistochemical analysis showed that the glutathione-S-transferase placental form (GST-P) positive foci promoted by I3C were suppressed by the administration of NAC. The mRNAs of members of the phase II nuclear factor, erythroid derived 2, like 2 (Nrf2) gene batteries, whose promoter region is called as antioxidant response element (ARE), were down-regulated in the DEN-I3C-NAC group compared to the DEN-I3C group, but Cyp1a1 was not suppressed in the DEN-I3C-NAC group compared to the DEN-I3C group. There was no marked difference in production of microsomal ROS and genomic 8-hydroxy-2′-deoxygunosine (8-OHdG) as an oxidative DNA marker between the DEN-I3C-NAC and DEN-I3C groups, while mapkapk3 and Myc were decreased by the NAC treatment. These results indicate that oxidative stress plays an important role for I3C's tumor promotion, and NAC suppresses induction of hepatocellular altered foci with suppressed cytoplasmic oxidative stress.

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Effect of Fenofibrate on Oxidative DNA Damage and on Gene Expression Related to Cell Proliferation and Apoptosis in Rats

Cited by 51 publications

References 37 publications

Twenty-six-week oral toxicity of diheptyl phthalate with special emphasis on its induction of liver proliferative lesions in male F344 rats

Twenty-six-week oral toxicity of diheptyl phthalate with special emphasis on its induction of liver proliferative lesions in male F344 rats

Impact of Gut Microbiota on Intestinal and Hepatic Levels of Phase 2 Xenobiotic-Metabolizing Enzymes in the Rat

Antioxidant N-acetyl-L-cysteine (NAC) supplementation reduces reactive oxygen species (ROS)-mediated hepatocellular tumor promotion of indole-3-carbinol (I3C) in rats

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